Composition for treatment of mia and method of preparing same



Patented Apr. 28, 1936 PATENT OFFICE COMPOSITION FOR TREATMENT OF MIAAND METHOD OF PREPARING SAME Arthur E. Meyer, Rockford, Ill., assignorto Chappel Bros., Inc., Rockford, 111., a corporation of Illinois NoDrawing. Application December 21, 1931, Serial No. 582,503

18 Claims.

This invention relates to a composition of matter useful in thetreatment of anemia and to a method for producing the same.

In anemic conditions, when the hemoglobin content of the blood is low,the supply of iron is a very important factor in the treatment for bloodregeneration and its effectiveness varies considerably with the form inwhich it is administered either alone or according to the well knownliver and iron therapy under the teachings of Whipple, Minot and Murphy,and others, wherein liver extract and some form of iron are administeredto the patient concurrently, either separately or mixed. A principaldifficulty in supplying this lies in the fact that under the conditionsexisting in the digestive system ordinary iron compounds are not readilyabsorbed. It is believed that in order to be absorbed the iron mustexist as either a soluble compound or as a relatively stable colloid ofvery small particle size. However, when iron is taken internally, assalts of either inorganic or organic acids they pass, during thedigestive process, from the stomach, which is acid in reaction, into theintestine, which is alkaline in reaction, whereupon the insolublehydroxide of iron is formed, in which condition the iron cannot beabsorbed. Doubtless, a small amount of iron is absorbed during thisprocess but not in sufficient quantity to effect the desired results.Furthermore, a large excess of iron salts must be given, most of whichpasses through the intestine without benefit to the patient. Many timesgastric disturbances caused by the use of these compounds did more harmto the patients than the benefits to be expected from the treatment.

Hemoglobin prepared from animals blood has been used for the purpose ofsupplying the iron in the so-called organic form. This has generallybeen considered beneficial but its effect has been small, dueprincipally to the low iron content of the material.

The present invention aims to provide a composition from which the ironis much more readily absorbed, which gives a better therapeutic effect,which is less irritating in its effect, and which has a lessobjectionable taste, and to provide a method for preparing thecomposition.

In preparing the composition I prefer to proceed substantially asfollows: Dissolve grams of dry ferrous chloride or grams of crystallizedferrous chloride (FeClzAHzO) in sufficient water to make cc. ofsolution. The exact volume of solution is not important except that thesolution should be concentrated. By keeping the solution of ferrouschloride in water very strong the degree of dissociation is small andthe rate of hydrolysis is maintained at as low a point as possible.Furthermore, it permits a more concentrated ultimate product to beformed. Ferrous sulfate, ferrous ammonium sulfate and other solubleferrous salts may be used instead of ferrous chloride or in additionthereto, but I have found them to be less desirable because of theirlower solubility and'their greater tendency to hydrolize producing aless stable product. This solution should be filtered into about 650 cc.of glycerine in order to remove insoluble matter such as oxychloridesand ferric oxide.

The mixture should then be stirred and the hydrogen ion concentrationadjusted by adding thereto with constant stirring a 10% solution ofcaustic alkali. This may be sodium hydroxide, potassium hydroxide,ammonium hydroxide or other non-poisonous hydroxide which does not yieldan insoluble compound with the iron solution. When ammonium hydroxide isused the concentration may be slightly greater than that equivalent to10% sodium hydroxide because of the difference in strength. By a 10%solution I mean one wherein 100 cc. of the solution contains 10 grams ofthe alkali. It is not essential that exactly a 10% solution of alkali beused but I have found it convenient to employ one of about thisconcentration for practical reasons. When the concentration of thealkali is too great there is a tendency for ferrous hydroxide to beprecipitated upon the addition of the alkali because of the difficultyof mixing the alkali into the iron solution with sufiicient rapidity. Onthe other hand, it is desirable to employ an alkali of as great astrength as is conveniently possible in order to avoid adding too muchwater. It is desirable that the water content of the mixture of ferrouschloride solution and glycerine be maintained at as low a point as ispractically possible since the more water contained in the glycerine theshorter the range in which the pH remains at 6.8. -In other words, thebuffer range of the glycerine is shortened as the percentage of waterincreases. For these reasons I have found about a 10% solution of alkalito be the most convenient for the purpose.

The hydrogen ion concentration of the ferrous chloride and glycerinesolution should be adjusted to about 6.8 on the pH scale by theindicator method using bromthymol blue as an indicator without dilutingthe solution. Preparing the solution as above described the followinggives an indication of the change of hydrogen ion concentration with theaddition of 10% sodium hydroxide. The original ferrous chloride andglycerine solution has a pH of less than 3.8. The

the indicators being bromcresol green, bromcresol purple and bromthymolblue, the tests being made without diluting the ferrous chloride andglycerine solution. It will be seen that the pH reaches 6.8 upon theaddition of 15 cc. of the 10% alkali and remains at 6.8 until more than26 cc. of alkali has been added. However, as previously stated, thegreater the amount of water contained in the ferrous chloride andglycerine the shorter will be this range in which the pH remains at 6.8.Solutions having a pH of 7 or more are unstable and solids willprecipitate therefrom in a day or so. Mixtures having a pH of 6.8 are ofan emerald green color and are stable over a long period of time if notexposed to the ain Upon dilution with water, however, a precipitate isusually formed the quantity of which depends upon the amount of alkalipresent. It is desirable to avoid weak solutions in order to be able toadminister the desired amount of iron in the smallest volume. However,where more dilute compositions are required it is advisable that morethan about A of the total liquid should consist of the solution of FeCl:in water, if a. wide buffer "range is to be maintained and the materialbe capable of dilution with protective colloids without precipitation.In other words, under these circumstances the mixture of ferrouschloride water and glycerine should contain not less than about 75%glycerine if it is to be reasonably stable.

I have found that a more effective composition, and one which is morestable, is formed if a reagent belonging to the group known asprotective colloids is added to the above solution. I can give notheoretical reason for this unless it be that the iron exists in thesolution in the colloidal state and that the colloid is stabilized bythe presence of the protective colloid which prevents precipitation ofthe iron upon standing and also acts to prevent the precipitation of theiron when the composition passes from the stomach into the intestinewhereby a greater percentage of the iron is absorbed. It is also quiteprobable that the protective colloid also exhibits a. buffer action. Ihave found blood serum to be particularly suited for this purpose and itmay be advantageously used as deflbrinated or citrated blood, or bloodwhich has otherwise been prevented from clotting, the latter beingparticularly desirable since it combines with the inorganic ironmixture, the organic iron of the hemoglobin. The blood serum not onlyacts as a protective colloid but serves as well to materially retard therate of oxidation of iron to the ferric state. When a solution having apH 6.8 formed with 20 cc. of NaOH, as explained, is diluted with twiceits volume of water, a dark green precipitate is formed immediately. I!it is diluted with serum in the same or any other proportion, the colorchange is about as one can expect from the mix ture of a yellow serumwith a weak green solution. No noticeable precipitation occurs.

Other colloids prevent the formation of a precipitate also, though to aless degree. The following colloids have been used: egg white, gelatin,starch, tragacanth gum, acacia gum. In each, the color quickly changesafter dilution to a deep green which turns more or less opaque onstanding. It is possible that the degree of effect of the other colloidsin keeping the ferrous hydroxide in the dispersed state depends on thedispersity of the protective colloid itself. Tragacanth, for instance,which does not form a very dispersed solution but which looks more likethe suspension of a gel in water, is of low protective eifect. Thesolution soon becomes turbid and is ready to let down a precipitate. A2% solution of gelatin is far better, the composition remainstransparent in a thin layer but is of a dark green color. The othercolloids used range between gelatin and tragacanth in efiectiileness.Their eflectiveness appears to depend largely on the concentration ofthe colloid and on its preparation, the latter of which has an importantinfluence on the degree of dispersion. It appears that blood serum, acolloid prepared by nature itself, is superior to artificially madecolloidal solutions. 7

The effect of the compositions on anemic dogs was recorded. Dogs of thesame litter, the blood of each having a hemoglobin content of 35%,Newcomer, were kept on an iron poor diet and the time required for theirrecovery to a normal hemoglobin content of 70% was noted. The controldog which was given no treatment aside from the iron poor diet, required28 days for recovery. A dog treated with a solution of ferrous chloridein glycerine in which the pH was not adjusted the dosage being theequivalent of 0.10 gram of iron per day required 14 days. The dogtreated at the rate of the equivalent of 0.10 gram of iron per day withthe solution of ferrous chloride in glycerine in which the pH wasadjusted as above described required only 8 days for recovery. Anotherdog of the same litter'with the same deficiency of hemoglobin whentreated with defibrinated blood alone required 11 days for completerecovery. A second series of tests were run in order to make acomparison between the value of deflbrinated blood alone and'defibrinated blood containing the neutralized solution of ferrouschloride in glycerine. In these tests the dogs all had a predetermineddeficiency of hemoglobin and the control dog required 21 days forcomplete recovery. A dog treated with the neutralized solution of ironin glycerine required 14 days and the dog treated with the mixture ofblood and the neutralized solution of iron in glycerine required 12days. These tests show a considerable superiority for the mixture ofblood and the neutralized solution of iron in glycerine. The results ofclinical tests in the treatment of anemia in human beings furthersubstantiate the results of the above mentioned tests.

-While I have given various theories toexplain the benefits andadvantages of my composition and certain words of description based onsuch theories, such theories are given only by way of description andillustration and I do not wish to be limited to any particular theory ormethod of operation, and I am aware that numerous alterations andchanges may be made in the composi 75 tion and methods disclosed withinthe spirit of the invention and the scope of the appended claims inwhich I claim:-

1. A composition for the treatment of anemia comprising a neutralizedsolution of a highly soluble, non-poisonous ferrous salt in watercontaining sufficient glycerine to normally prevent precipitation of theiron.

2. A composition for the treatment of anemia comprising a neutralizedsolution of ferrous chloride in water containing sufllcient glycerine tonormally prevent precipitation of the iron.

3. A composition for the treatment of anemia comprising a neutralizedsolution of a highly soluble, non-poisonous ferroussalt in watercontaining sufficient glycerine to normally prevent precipitation of theiron to which solution has been added a protective colloid.

4. A composition for the treatment of anemia comprising a neutralizedsolution of ferrous chloride in water containing sufficient glycerine tonormally prevent precipitation of the iron to which solution has beenadded a protective colloid. l

5. A composition for the treatment of anemia comprising a neutralizedsolution of a highly soluble, non-poisonous ferrous salt in watercontaining suflicient glycerine to normally prevent precipitation of theiron towhich solution has been added a protective colloid consisting ofblood serum.

6. A composition for'the treatment of anemia comprising a neutralizedsolution of ferrous chloride in water containing sufilcient glycerinetonormally prevent precipitation of the iron to which solution has beenadded a protective colloid consisting of blood serum.

7. A composition for the treatment of anemia comprising a neutralizedsolution of ferrous chloride in water containing sufiicient glycerine tonormally prevent precipitation of the iron to which solution has beenadded a protective colloid consisting of defibrinated blood.

8. A composition for the treatment of anemia comprising a neutralizedsolution of ferrous chloride in a mixture of water and glycerinecontaining at least about 75% of glycerine.

9. A composition for the treatment of anemia comprising a neutralizedsolution of ferrous chloride in a mixture of water and glycerine towhich blood serum has been added, said mixture containing at least 75%of glycerine.

10. A composition for the treatment of anemia comprising a neutralizedsolution of ferrous chride in water and glycerine in the proportions ofat least 40 grams of ferrous chloride to 100 cc. of water and at" least300 cc. of glycerine.

11. A composition as set forth in claim 10 containing blood serum.

12. A method of preparing a composition for the treatment of anemiacomprising preparing a concentrated solution of a highly soluble,nonpoisonous ferrous salt-in water, mixing therewith sufiicientglycerine to normally prevent precipitation of the iron whenneutralized, and neutralizing said mixture.

13. A method of preparing a composition for the treatment of anemiacomprising preparing I the treatment of anemia comprising preparing aconcentrated solution of ferrous chloride in water, mixing therewithsuflicient glycerine to normally prevent precipitation of the iron whenneutralized, neutralizing said mixture, and adding a protective colloidconsisting of blood serum.

16. A method of preparing a composition for the treatment of anemiacomprising preparing a concentrated solution of ferrous chloride inwater,

mixing therewith suflicient glycerine to normally prevent precipitationof the iron when neutralized, neutralizing said mixture, and adding aprotective colloid consisting of defibrinated blood. '17. A method ofpreparing a composition for the treatment of anemia comprising preparinga concentrated solution of ferrous chloride in water, mixing therewithsuflicient glycerine to normally prevent the precipitation of the ironwhen neutralized, and neutralizing said mixture by adding thereto asolution of a reagent taken from the group sodium hydroxide, andpotassium hydroxide.

18. A composition for the treatment of anemia comprising a substantiallyneutral solution of ferrous chloride and a hydroxide taken from thegroup sodium hydroxide and potassium hydroxide in water containingsufilcient glycerine to'normally prevent precipitation of the iron.

